Lysosomal cathepsins and their regulation in aging and neurodegeneration
Open accessAbstract
Lysosomes and lysosomal hydrolases, including the cathepsins, have been shown to change their properties with aging brain a long time ago, although their function was not really understood. The first biochemical and clinical studies were followed by a major expansion in the last 20 years with the development of animal disease models and new approaches leading to a major advancement of understanding of the role of physiological and degenerative processes in the brain at the molecular level. This includes the understanding of the major role of autophagy and the cathepsins in a number of diseases, including its critical role in the neuronal ceroid lipofuscinosis. Similarly, cathepsins and some other lysosomal proteases were shown to have important roles in processing and/or degradation of several important neuronal proteins, thereby having either neuroprotective or harmful roles. In this review, we discuss lysosomal cathepsins and their regulation with the focus on cysteine cathepsins and their endogenous inhibitors, as well as their role in several neurodegenerative diseases.
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Emerging genetic, neuropathological, and biological evidence implicates dysfunction of the endosomal-lysosomal pathway in AD pathogenesis at early and late stages of disease and in other late-onset neurodegenerative diseases.
“Emerging genetic, neuropathological, and biological evidence implicates dysfunction of the endosomal-lysosomal pathway in AD pathogenesis at early and late stages of disease (Nixon, 2017) as well as in other late-onset neurodegenerative diseases (Nixon, 2013;Stoka et al., 2016;Vidoni et al., 2016;Colacurcio et al., 2018).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Stoka et al., 2016
At least five other PD-associated genes (LRRK2, UCHL2, VCP35, DJ-1, and SNCA) affect CMA.
“At least five other genes that are associated with PD (but not LSDs) also affect CMA: LRRK2, UCHL2, VCP35, DJ-1, and SNCA, which encodes alpha-synuclein.149–153”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [149]
Section 4 (Autophagy; page unavailable) identifies CMA as an autophagy pathway, and §6.3 (Parkinson’s disease; page unavailable) discusses α-synuclein in PD. Neither passage says that SNCA or the other four named genes affect CMA; searches for those genes and chaperone-mediated autophagy found no such link in our copy. (LLM, conf=0.74)
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References 268 · Cited by 334
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- Authors
- Stoka, V., Turk, V., & Turk, B.
- Affiliations
- Jožef Stefan Institute (SI)
- University of Ljubljana (SI)
- Corresponding author
- Stoka, Veronika
- Turk, Boris
- Venue
- Ageing Research Reviews
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 32
- Pages
- 22-37
- ISSN
- 1568-1637 (ISSN-L)
- OpenAlex
- W2346760531
- Cited by
- 334
- References
- 268
- Citations by year
- 2026: 14 · 2025: 34 · 2024: 31 · 2023: 30 · 2022: 38 · 2021: 46 · 2020: 44 · 2019: 43 · 2018: 20 · 2017: 27 · 2016: 6 · 2013: 1
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Ageing Research Reviews (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Slovene Research Agency (P1-0140, J1-6739)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- lysosomal cathepsins, cysteine cathepsins, lysosomal enzymes, brain aging, neurodegeneration, autophagy, neuronal ceroid lipofuscinosis, cathepsin inhibitors, lysosomal proteases, protein degradation, neuroprotection
- MeSH terms
- Aging, Animals, Autophagy, Brain, Cathepsins, Humans, Lysosomes, Neuronal Ceroid-Lipofuscinoses
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